Vantage Snippets are short summaries of breaking news stories.
Phase III results toplined yesterday suggest that Abbvie’s Jak inhibitor Rinvoq might be the most efficacious atopic dermatitis therapy in late-stage trials. Moderate to severe eczema patients receiving 15mg or 30mg of Rinvoq monotherapy in the Measure Up 1 trial showed statistically significantly better skin clearance than those given placebo. A cross-trial comparison of Rinvoq’s scores on the study’s co-primary endpoints – a minimum 75% improvement in the eczema area severity index (EASI 75) and a validated investigator’s global assessment (IGA) for atopic dermatitis of 0 or 1, representing clear or almost clear skin – show it surpassing Pfizer’s Jak, abrocitinib, in its phase III trials. It also easily beats Sanofi/Regeneron’s market leader, Dupixent. As with all Jaks safety is key, and here the news is cheering for Abbvie, with the rate of serious adverse events identical in the high-dose and placebo groups. Less than 1% of Rinvoq patients had serious infections versus none on placebo, and there were no deaths, venous thromboemboli or major cardiac events. If the several other ongoing phase III eczema trials post similarly decent data, Rinvoq could find a niche as second-line, post-Dupixent, therapy.
|Rinvoq's phase III trials in moderate to severe eczema|
|Trial details||N||PCD||Trial ID|
|Monotherapy, vs placebo (Measure Up 1)||810||Jan 2021||NCT03569293|
|Monotherapy, vs placebo (Measure Up 2)||810||Jan 2021||NCT03607422|
|Monotherapy, vs Dupixent and placebo (Heads Up)||692||Sep 2020||NCT03738397|
|Open-label extension to Heads Up||600||Jul 2021||NCT04195698|
|Combo w topical corticosteroids, vs placebo||272||Feb 2022||NCT03661138|
|Combo w topical corticosteroids, vs placebo (AD Up)||810||Aug 2022||NCT03568318|
|PCD=Primary completion date. Source: EvaluatePharma.|
Generic competition for Biogen’s biggest seller, the multiple sclerosis drug Tecfidera, could come as soon as next year – seven years earlier than expected. Yesterday the West Virginia District court ruled in favour of Mylan, deeming Tecfidera’s ’514 patent invalid, a development that caused Biogen’s shares to fall 7.5%. Biogen intends to appeal against the decision, and this process could take 12-18 months. It is not yet clear whether Mylan will launch its generic at risk, but the company noted that it was working with the US FDA to accelerate the approval date, currently November 16. Beyond its marketed drugs Biogen has a thin pipeline and thus its reliance on the controversial Alzheimer’s project aducanumab, due to be filed in the coming quarter, is building.
|Biogen's biggest products ranked on NPV|
|Product||Therapy area||2026e sales ($bn)||Today's NPV||Status|
|Spinraza||Spinal muscular atrophy||1.3||5.7||Marketed|
|Aducanumab||Alzheimer's disease||1.7||5.0||Phase III|
|Other marketed drugs||3.3||12.9|
|Other R&D projects||0.5||2.4|
|Total for Biogen||11.6||53.5|
|Biogen market cap||42.4|
|Note: sellside forecasts predate the Tecfidera patent loss ruling. Source: EvaluatePharma.|
Abbvie wants to bolster its lupus game, and in the process has given Alpine Immune Sciences its first big pharma vote of confidence. Alpine is a Seattle-based biotech focused on antibodies against novel immune system targets, or novel ways of hitting known targets, run by Mitchell Gold, the former chief exec of the now-defunct cell therapy company Dendreon. Today’s deal with Abbvie gives Alpine $60m up front for an option over ALPN-101, a CD28/Icos antagonist MAb that had been positioned against autoimmune diseases, and had shown tolerability in a volunteer study. Abbvie now wants to pit it against systemic lupus erythematosus, but Alpine will first have to fund a phase II study; the biotech could get another $75m in milestones before a formal deal is signed, a move that would trigger a $75m exercise fee. Abbvie’s BTK inhibitor ABBV-105 is in phase II in lupus, but the Ablynx-derived vobarilizumab failed. Orencia, which acts on CD28, and the Icos ligand blocker prezalumab had unsuccessfully been studied in the disease, but Alpine says ALPN-101 is a potentiator rather than just a dual blocker of these pathways. Alpine, which listed by reverse merger in 2017, saw its stock open up 170%.
If Tecentriq’s breakthrough in first-line triple-negative breast cancer ultimately ended up somewhat muted, Roche now has a chance to reassert its authority. This is courtesy of the neoadjuvant Impassion-031 study, which today read out positively for pathological complete response. Tecentriq plus Abraxane is approved for first-line TNBC, but only in patients expressing PD-L1 at 1% or greater, as a result of the Impassion-130 trial, whose marginal all-comers benefit disappointed (Tecentriq gets its narrow breast cancer label, March 11, 2019). However, Impassion-030, in which Tecentriq plus Abraxane-containing chemo was given before surgery, has shown a benefit versus chemo alone regardless of PD-L1 expression, Roche says. The full data, including the extent to which PD-L1 expressers drive the overall benefit, have yet to be scrutinised, but Impassion-031 might allow Roche to establish Tecentriq as a standard in an all-comers setting, ie before that of Impassion-131, which would accordingly become less important. This could also neutralise the threat of Merck & Co’s Keytruda, whose TNBC successes comprise the front-line Keynote-355 trial, albeit in ≥10% PD-L1 expressers, and Keynote-522, a neoadjuvant/adjuvant study. And Tecentriq’s failure in another neoadjuvant trial, NeoTRIPaPDL1, now becomes easier to dismiss.
|Roche trials in triple-negative breast cancer|
|Impassion-031||Tecentriq + Abraxane vs Abraxane||pCR in PD-L1+ and all-comers||Toplined positive in PD-L1+ and all-comers|
|Neoadjuvant + adjuvant|
|NeoTRIPaPDL1||Tecentriq + Abraxane vs Abraxane||EFS||Failed in Dec 2019|
|MO39875||Tecentriq + chemo vs chemo||pCR & EFS||Dec 2023 primary completion|
|Impassion-030||Tecentriq + chemo vs chemo||iDFS||Jan 2022 primary completion|
|Impassion-130||Tecentriq + Abraxane vs Abraxane||OS & PFS in PD-L1+ and all-comers||Approved in ≥1% PD-L1|
|Impassion-131||Tecentriq + paclitaxel vs paclitaxel||PFS in PD-L1+ and all-comers||Upsized by 11%, completion delayed from Feb to Nov 2019; still no data|
|Impassion-132||Tecentriq + chemo vs chemo||OS in PD-L1+ and all-comers||Upsized by 63%, completion delayed from Jul 2019 to Jan 2023|
|Ipatunity-130||Ipatasertib + chemo vs chemo||PFS in PIK3CA/AKT1/PTEN-altered||Dec 2021 primary completion|
|Source: clinicaltrials.gov & company presentation.|
When the Pallas study of Pfizer’s Ibrance failed in high risk early breast cancer at the beginning of the month, expectations around Eli Lilly’s similar trial of Verzenio, MonarchE, plunged. Surprise all round today when an interim analysis from MonarchE showed that adding Verzenio to standard adjuvant endocrine therapy significantly decreased the risk of recurrence or death, over hormone therapy alone. The actual benefit remains important to know however Lilly described the results as definitive. The company's decision to enrol patients with relatively severe disease – at least four lymph nodes positive or 1-3 nodes positive plus either tumours greater than 5cm in size, grade 3 histology or high risk of recurrence – has paid off. Pfizer enrolled a broader population in Pallas, hoping for a bigger ultimate market, but the likeliest outcome now is that Verzenio will be the first CDK 4/6 to market, probably next year, with any sort of early breast cancer indication. The Penelope-B trial of Ibrance, again in a broad group, is still running with data expected later this year. Lilly’s shares surged 13% in early trade, adding a huge $18bn to the company's market cap.
|Selected trials of CDK 4 & 6 inhibitors in early breast cancer|
|Group||Drug||Trial||Details||N||Results||2026e BC sales ($m)|
|Lilly||Verzenio||MonarchE||Verzenio + ET vs. ET alone in resected node-positive, early stage HR+, HER2- invasive BC||4,580||Interim hit on recurrence or death||2,596|
|Pfizer||Ibrance||Pallas||Ibrance for 2 years + ET vs. ET alone in HR+/HER2- stage II or III early invasive BC||5,794||Stopped for futility||11,036*|
|Pfizer||Ibrance||Penelope-B||Ibrance + ET in HR+/HER normal patients with residual disease after neoadjuvant chemotherapy and surgery||1,250||Expected early 2021||11,036*|
|Novartis||Kisquali||Natalee||Kisqali + ET or ET alone in patients with stage II or III HR+/HER2- early BC||4,000||2025||1,470|
|ET=endocrine therapy; BC=breast cancer. * Forecasts predate Pallas halt for futility. Source: EvaluatePharma, clinicaltrials.gov.|
A successful mid-stage read out from Momenta’s anti-FcRn project, nipocalimab, confirms that the project is a viable competitor in this closely-watched novel mechanism. The Vivacity-MG study compared four different dosing schedules of the antibody against placebo in patients with advanced myasthenia gravis (MG), an IgG-driven autoimmune condition. The primary efficacy endpoint was change on a symptom scale called MG-ADL, and when pooled across the arms the placebo-adjusted response rate came out remarkably close to that achieved by Argenx last month with its leading anti-FcRn project, efgartigimod: 36.5% vs 40% respectively. Safety also looked clean, reassuring given some signals seen in phase I; Momenta shares jumped 15% on the news. Seeking a competitive edge the company hopes to take monthly or longer dosing into phase III trials, which are slated to start later this year. Subcutaneous delivery remains the real goal, however, and both Argenx and Momenta are working on switching to SC from their current IV formulations. One wild card here is Immunovant, which is gearing up to release phase IIa data on its SC project, IMVT-1401, in the coming months.
|FcRn targeted projects: the progress so far|
|Efgartigimod||Anti-FcRn Ab fragment; IV and SC in earlier development||Argenx||US filing due by year end|
|Rozanolixizumab||Anti-FcRn MAb; SC||UCB||Phase III readout expected H1 2021|
|Anti-FcRn MAb; IV and SC in earlier development||Momenta||Phase II MG trial positive, phase III to start by YE'20|
|IMVT-1401||Anti-FcRn MAb; SC||Immunovant/ Hanall Biopharma/ Harbour Biomed||Phase IIa in MG read-out Q3'20; thyroid eye disease over next 12 mth|
|ALXN1830||Anti-FcRn MAb; IV and SC in earlier development||Alexion (Syntimmune)||Paused owing to Covid-19, to restart 2021, SC formulation prioritised|
|ABY-039||Anti-FcRn bivalent Ab mimetic; SC||Affibody||Alexion handed back rights in Feb 2020; phase I ongoing|
|Source: EvaluatePharma, company statements.|
Welcome to the era of the prescription video game. The FDA has cleared for market the first ever such project – EndeavorRx, designed by Akili to treat children aged children 8 to 12 with attention deficit hyperactivity disorder in conjunction with medication or educational programmes. Analysts from Jefferies, covering Akili’s parent company Puretech, believe the approval validates Akili’s cognitive interference processing platform, which is also used with the phase II projects AKL-T02 for paediatric autism and AKL-T03 for multiple sclerosis. The analysts peg peak sales of EndeavorRx at $300m in the US alone, reflecting the appeal to parents of a non-drug treatment for their children, as well as the game’s decent showing in its pivotal trial. But these are unproven technologies as far as their commercial model is concerned; exactly how they will be paid for and whether reimbursement is obtainable are hurdles yet to be jumped. Still, the clearance of EndeavorRx via the FDA’s de novo pathway creates a new class of digital therapeutics which should smooth the path of future prescription computer games. EndeavoRx will soon be available to download from various app stores, Akili says, along with a related mobile tracking app called Akili Care.
The FDA continues to wave through at pace new tests for Covid-19 under its emergency use programme. Last week saw the arrival of the first diagnostic to incorporate a genomic analysis of a patient’s specific viral infection, from diagnostics giant Illumina. It is generally accepted that only one strain of Sars-CoV-2 is circulating, and while several mutations have been identified none seem to have had any impact on virus biology or function. This could change, of course, and it will become only more crucial to closely monitor the virus as potential treatments and vaccines approach the market. As such, genetic sequencing of samples will allow researchers to identify and track any mutations that the virus might undergo. The Illumina COVIDSeq test is run on the company’s next-generation sequencing system, NovaSeq 6000, and can deliver results within 24 hours, the company said; each run can accommodate just over 3,000 samples. Illumina said that availability is limited at the moment, although wider roll out will happen over the summer.
|Note: "Other" includes one antigen test, one home sampling kit and one IL-6 test.|
Astrazeneca’s spinout Viela Bio gained its first approval yesterday: that of inebilizumab, trademarked Uplizna, for the rare autoimmune condition neuromyelitis optica spectrum disorder. However, extensive off-label use of rituximab could be a barrier to adoption. Both rituximab and Uplizna are B-cell-depleting therapies, and payers could require patients to take rituximab, including biosimilars, before more expensive treatments like Uplizna are considered. If that is the case, and a patient were to fail on a relatively cheap B-cell depleter, physicians might choose to move to a different mechanism of action – such as Alexion’s Soliris, an anti-C5 MAb approved last year – instead of using a second, more expensive B-cell-depleting agent. Other projects are vying for the US market, which comprises 4,000-8,000 patients; Roche’s satralizumab has been filed in the indication, and ultomiris, a follow on to Soliris, is in phase III.
Neuromyelitis optica landscape
|Project||Company||Target||Setting||Reduction in attack risk (study)||Treatment/ placebo adverse event rate||2026e NMO sales||US status|
|Mainly add-on||94% in AQP4+(Prevent)||92%/91%||$488m||Approved in AQP4 + patients|
Roche (also biosimilars)
|CD20||Mono or combo||70-89% (various)||90%/90%||-||Used off-label|
73%, 77% in AQP4+ (N-Momentum)
|72%/73%||$586m||Approved in AQP4 + patients|
|IL-6||Add-on||62% (SakuraSky)||90%/95%||$431m||FDA filing accepted last October|
|Mono||74% in AQP4+ (SakuraStar)||92%/75%|
|Add-on||? AQP4+(NCT04201262)||?||$264m||Phase III primary completion Nov 2021|
|AQP4 = aquaporin 4 antibody, a key biomarker for disease found in around 80% of NMOSD patients.
Source: Company releases, Stifel & EvaluatePharma.
Anyone marvelling at the speed with which the first antibody against Covid-19 entered the clinic will note that the development pace has not slowed. Since Evaluate Vantage covered this space barely a week ago two further projects, from Lilly/Junshi and from Regeneron, have entered phase I. Not to be outdone, the first antibody into the clinic, Lilly/Abcellera’s LY-CoV555, is about to start phase II, an entry just unveiled on Clinicaltrials.gov reveals. While phase I is in hospitalised patients, the phase II study, due to begin tomorrow, will enrol 400 mild to moderate Covid-19 subjects. LY-CoV555 will be compared against placebo in a double-blind fashion, with change in day-11 Covid-19 viral load as primary endpoint. The separate Lilly/Junshi project, JS016, which binds a different epitope on the virus’s spike protein, is now in a healthy volunteer trial. Meanwhile, Regeneron’s multi-antibody cocktail REGN-COV2 has started its first two phase I studies, also in hospitalised and non-hospitalised patients. The combo has been revealed to comprise two antibodies, REGN10933 and REGN10987, and two more trials in the prophylactic setting (in healthcare workers and in people with close exposure to a Covid-19 patient) are planned, Regeneron says.
|Selected antibodies and related biologicals in development for Covid-19|
|Companies||Lead, if identified||Mechanistic approach||Clinical development?|
|Lilly/Abcellera||LY-CoV555/ LY3819253||IgG1 MAb vs spike protein||Ph2 study in mild to moderates|
|Ph1 study in hospitalised subjects|
|Regeneron||REGN10933 + REGN10987||Two-Ab cocktail; prophylaxis trials due||Ph1 trial in hospitalised subjects|
|Ph1 trial in ambulatory subjects|
|Lilly/Junshi||JS016||Fully human MAb vs spike protein||Ph1 in volunteers|
|Sab Biotherapeutics||SAB-185||Polyclonal||Clinical trial due mid-2020|
|Celltrion||CT-P59||MAb vs spike protein receptor binding domain||Clinical trial due Jul 2020|
|Glaxosmithkline/Vir||VIR-7831 & VIR-7832||MAbs vs spike protein||Clinical trial in Jul-Sep 2020|
|Astrazeneca||–||MAbs, incl based on recovered patients||Clinical trial in Jul-Sep 2020|
|Sorrento||STI-1499||Fully human MAb vs spike protein||Clinical trial due Q3 2020|
|Brill Bio||–||Fully human MAb||Clinical trial due Q3 2020|
|Yumab||–||MAbs, incl based on recovered patients||Clinical trial due H2 2020|
|Molecular Partners||–||Darpin proteins||Clinical trial due H2 2020|
|Systimmune||SI-F019||Bivalent Ace2 fusion protein vs spike protein||IND filing due 2020|
|Atreca/Beigene/IGM||–||IgM & IgA MAbs vs novel epitopes||–|
|Amgen/Adaptive||–||MAbs based on recovered patients||–|
|Ossianix||–||Single-domain VNAR MAbs vs spike protein||–|
|Sorrento||STI-4398||Ace2-Fc protein vs spike protein||–|
|Sorrento/Mabpharm||STI-4920||Bispecific vs 2 domains on spike protein||–|
|Fusion Antibodies||–||Fully human MAb vs engineered Ace2 protein||–|
|Fusion Antibodies||–||Fully human MAb vs spike protein||–|
|Virna||–||Neutralising Abs vs spike protein||–|
|Note: excludes anti-IL6, anti-GM-CSF and other MAbs not directly targeting Covid-19.|